Three centers (Harvard Medical School-MGH, Johns Hopkins Medical School- JHU, and the University of Alabama at Birmingham Medical Center-UAB) have successfully collaborated in the collection of 219 familial Alzheimer's disease (FAD) families (400 families will ultimately be collected) by designing and implementing a common protocol and consensus diagnostic procedures. These same three centers will continue to work together to achieve a common goal, i.e., identifying genes involved in FAD. They will share the task of screening the human genome. MGH has responsibility for chromosomes 3, 4, 9, 12, 17, 19, 20, and 22, JHU for chromosomes 2, 5, 8, 11, 13, 18, 21, and Xq, and our center for 1, 6, 7, 10, 14, 15, 16, Xp, and Y. In order to accomplish this common goal the following specific aims are proposed 1) genotype the 400 families using polymorphic simple sequence repeat (SSRs) Index Markers by polymerase chain reaction and acrylamide gel electrophoresis, 2) test for linkage of all families to chromosome 14q24 markers and test for SSCP mutations and SSR polymorphisms (especially trinucleotide unstable expansion repeats) in the candidate genes; HSP70 and c-FOS, for linkage to AD, 3) test all the families for mutations in any of the exons for the amyloid precursor protein, especially those in exon 17, using single strand conformational polymorphism (SSCP), 4) Screen for an elevated ApoE4 allele frequency in AD cases and test for linkage to markers linked to the ApoE/ApoCl/ApoCll cluster, 5) Pursue novel genes and DNA markers found to be genetically linked to AD and candidate genes found to have a role in FAD or memory, 6) perform computer simulations to determine the power of these linkage methods under various assumptions concerning the genetic mode of inheritance, age of onset distribution, and most importantly degree of heterogeneity 7) Perform linkage analyses using likelihood and model free methods (Sib-pair and affected pedigree), and confirm positive linkages using multipoint mapping and multipoint APM, 8) if no additional linked markers are present develop new linked markers for this multipoint mapping and 9) Maintain genotyping data and linkage results on the TRl-AD database. The finding of new map regions which harbor FAD susceptibility genes especially late onset genes will allow us to search these regions for additional candidate genes and apply positional cloning strategies to clone AD genes, as well as to subdivide the FAD population genetically which may lead to the identification of more homogeneous clinical subtypes, and ultimately to more effective targeting of therapeutic regimens.